The NOP (Nociceptin/Orphanin FQ peptide) receptor, the fourth opioid receptor subtype, mediates distinctive actions in non-human primates that suggest the possiblity that activity at this receptor may result in strong analgesia in the absence of virtually all of the side effects that are found in mu opioid receptor (MOP) agonists. NOP agonists, either peptidic or non-peptidic, produce full analgesia in each of the three assays that we use in rhesus monkeys, when delivered locally, systemically, or intrathecally. Yet small molecule NOP agonists do not serve as reinforcers. Furthermore, our preliminary data indicate that these agonists may not produce acute dependence or reduce gastrointestinal transit. Finally, we have found that combinations of MOP partial agonists and NOP agonists have a synergistic action to reduce nociceptive responses in our monkey model. These exciting results prompt this proposal to evaluate novel NOP agonists that have been synthesized by Dr. Zaveri in side-by-side comparisons with MOP agonists and the currently available NOP agonists in a number of assays in rhesus monkeys. These assays have been designed specifically to reflect the therapeutic (analgesia) and side effect (abuse liability, aversive effects, interoceptive stimulus effects, gastrointestinal transit, physiological changes and physical dependence) profile of opioid analgesics. Many of these assays were developed in this laboratory and have been validated over the course of a decade or more. The gastrointestinal transit assay is novel and is being developed specifically to indicate the likelihood that NOP agonists lack the constipating effects of MOP agonists. In the first aim of this proposal, full and partial selective NOP agonists will be evaluated and compared. In the second aim, mixed NOP/MOP agonists with high affinity and differing efficacies at the two receptors will be examined in the assays. The possibility that drugs with agonist actions at both receptors will be potent and effective analgesics with reduced side effects encourages our evaluation of these mixed agonists. Our unique set of assays in rhesus monkeys, our extensive history of research on these models in these animals, in combination with the availability of a number of exciting novel NOP- related ligands, sets the stage for the identification of a breakthrough in the treatment of pain in the clinical population. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it could result in the identification of abuse-free and constipation-free strong analgesics whose effects are mediated through the fourth opioid receptor subtype, the NOP receptor. Identification of a superior analgesic with fewer side effects has long been a goal of pain management, and such drugs could profoundly impact human suffering as well as reducing the risks of drug abuse that are posed by the currently available strong opioid analgesics.